Controlled release oral drug delivery system

ABSTRACT

The invention relates to synchronous drug delivery composition comprising a polymeric matrix which comprises hydrogel blended with a hydrophobic polymer, so as to form an erodible matrix, a drug, and, optionally, an agent which enhances intestinal drug absorption and/or an agent which inhibits intestinal drug degradation,  
     wherein erosion of the erodible matrix, permits synchronous release of the drug, the hydrogel and the intestinal drug absorption agent and/or the agent which inhibits intestinal drug degradation.

FIELD OF THE INVENTION

[0001] The invention relates to a pharmaceutical system aimed atincreasing the bioavailability of orally administered drugs belonging tothe following categories: (a) large molecular weight drugs, (b) drugsthat lose their potency in the gastrointestinal (GI) tract as a resultof enzymatic degradation.

BACKGROUND OF THE INVENTION

[0002] In the following paragraphs protein drugs will be discussed astypical examples of drug molecules that are either large molecules orhighly susceptible to enzyme degradation. However, additionalnon-proteinous drugs can be included in this group and they will bediscussed later.

[0003] Medical use of protein drugs is constrained by three majordrawbacks. The first is their short biological half-life which requires,in some cases, frequent administrations. The second is the rapiddegradation which occurs in mucosal tissues that generally cover thebody cavities. Lastly, most protein drugs are large molecules andtherefore do not easily cross the intestinal epithelium. Therefore, themost common mode of protein drugs administration is the parenteralroute. However, apart from the inconvenience to the patients, parenteraldelivery systems are also more expensive in terms of production and drugadministration. There is therefore a need for an effectivenon-parenteral mode of administration of protein drugs that will provideprotection against biological degradation and/or enhance its transportacross mucosal barriers. Although sophisticated non-parenteralpharmaceutical systems, such as intra-nasal systems, have beendeveloped, oral administration is more favorable, having the majoradvantage of convenience for increased patient compliance. Sometimesoral administration of peptides offers physiological advantages, forexample oral administration of insulin is superior to parenteraladministration because, like the native hormone secreted by thepancreas, it also drains primarily into the portal vein to exert itsinitial effect on the liver. Some insulin will then find its way intothe peripheral circulation via lymphatic channels [Goriya, Y., et al.,Diabetologia 19:454-457 (1980)]. In contrast, injected insulin isdrained entirely into the peripheral circulation and has access to allparts of the body. Notwithstanding these advantages, most protein drugshave not been orally delivered to date because of the lack of a simpleand reliable drug delivery system that will be able to overcome thebiological and physico-chemical constraints mentioned above.

[0004] An effective oral carrier for protein drugs should (a) shield itscontent against the luminal and brush border peptidases and (b) becapable of facilitating the uptake of the protein drug—usually a largemolecular weight entity—across the gastrointestinal (GI) epithelium.Many studies have reported that protein drugs such as insulin,vasopressin, calcitonin, enkaphalins and thyrotropin-releasing hormone(TRH) were administered relatively successfully via the oral route [Lee,V. H. L., et al., Oral Route of Peptide and Protein Drug Delivery, in V.H. L. Lee (Ed.): Peptide and Protein Drug Delivery, Marcel Dekker, 1991New York, pp 691-738]. An increase in the bioavailability of proteindrugs after oral administration can be accomplished by theco-administration of either peptidases inhibitors, to help keep theprotein drug as intact as possible at the site of absorption, or ofprotein absorption enhancers. Some works report the use of bothabsorption enhancers and peptidase inhibitors in the same formulation[e.g. Ziv, E., et al., Biochem. Pharmcol. 3:1035-1039 (1987)]. Sometypical examples of oral administration of the protein drug insulintogether with peptidase inhibitors or absorption enhancers are listedbelow.

[0005] Morishita et al. [Int. J. Pharm. 2&: 1-7 (1992)] found that afterformulating insulin together with protease inhibitors such as trypsininhibitor, chemostatin, Bowman-Birk inhibitor and aprotinin intoEudragit L-100^(R) microspheres, the insulin was resistant to pepsin,trypsin and α-chymotrypsin in vitro. However, in similar experimentsperformed in vivo by Laskowski and coworkers in which insulin wasinjected together with soybean trypsin inhibitor (SBTI) or,alternatively, without any inhibitor, a very small pharmacodynamicresponse was observed [Laskowski, M., Jr., el al., Science 127:1115-1116(1958)]. Similar results were observed by Danforth and coworkers whoalso found that diisopropylfluorophosphate was an effective depressantof insulin digestion, while SBTI was not [Danforth, E., et al.,Endocrinology 65:118-123 (1959)]. In contrast, it was found that theaddition of SBTI solution boosted the pharmacological effect of insulin,namely reduction of blood glucose level, after its injection into thelumen of rat ileum [Kidron, M., et al., Life Sci. 31:2837-2841 (1982)].Takahashi et al. used decanoic acid to enhance the absorption of thehydrophilic non-absorbable marker phenol sulfon phthalate. They foundthat the absorption correlated to the rate of disappearance of thedecanoic acid from the intestine. The absorption onset was within fewminutes. This indicates that there is a rationale to apply an absorptionenhancer for improved functioning of the delivery system.

[0006] Table A and Table B hereunder itemize some examples of absorptionenhancers and protease inhibitors reported in the literature. TABLE AClasses of enhancers tested to promote drug absorption in the GI tractand some of their representatives (References listed after Table A)CLASS EXAMPLES NSAID (non-steroidal Sodium salicylate antiinflammatorySodium 5-methoxysalicylate drugs) and derivatives IndomethacinDiclofenac Surfactants Nonionic: polyoxyethylene ethers Anionic: sodiumlaurylsulfate Cationic: quaternary ammonium compounds Bile saltsDihydroxy bile salts: Na deoxycholate Trihydroxy bile salts: Na cholateMedium-chain fatty acids Octanoic acid Decanoic acid Medium-chainglycerides glyceryl-1-monooctanoate glyceryl-1-monodecanoate EnaminesDL-phenylalanine ethylacetoacetate enamine Mixed micelles Glycerylmonooleate + Sodium taurocholate Linoleic acid + HCO60 Calcium bindingagents EDTA Phenothiazines Chlorpromazine Liposomes Azone Fatty acidderivatives of Palmitoyl-DL-carnitine carnitine and peptidesN-myristoyl-L-propyl-L-prolyl-glycinate Saponins Concanavaline APhosphate and phosphonate DL-α-Glycerophosphate derivatives3-Amino-1-hydroxypropylidene-1,1- diphosphonate Polyacrylic acidDecanoic acid

REFERENCES

[0007] van Hoogdalem E. J. et al., Pharmac. Ther. 44:407-443 (1989);

[0008] Muranishi S., Crit. Rev. Ther. Drug Carrier Sys., 7:1-34 (1990);

[0009] Geary, R. S. and Schlemeus, H. W., J. Contr. Release, 23:65-74(1993);

[0010] Touitou, E. and Rubinstein A., Int. J. Pharm. 30:95-99 (1986);

[0011] Kraeling, M. E. K. and Ritschel, W. A., Meth. Find. Exp. Clin.Pharmacol. 14:199-209 (1992)].

[0012] Takahashi, K. et al., Pharm. Res. 11:388-392 (1994);

[0013] Takahashi, K. et al., Pharm. Res. 11:1401-1404 (1994);

[0014] Hochman, J. H. et al., J. Pharmacol. Ex. Ther. 269:813-822(1994). TABLE B Examples of protease inhibitors used in oralformulations of peptide drugs SUBSTRATE REFERENCE Aprotinin Kidron etal. Life Sci. 31:2837 (1982); Morishita, M. et al., Int. J. Pharm. 78:1-7 (1992) SBTI Laskowski et al. (1958) ibid; Danforth et al. (1958)ibid; Kidron et al. (1982) ibid; Bowman-Birk inhibitor Morishita et al.(2) (1992) ibid. Polycarbophil Borchard G. et al., Proceedings of the7th International Symposium on Recent Advances in Drug Delivery Systems,Salt Lake City, Utah, February-March, 1995, pp. 7-10. Bowman- Morishitaet al., Int. J. Pharm. 78: 1-7 (1992) Birk inhibitor

[0015] Absorption enhancement has been found to be very efficient in theimprovement of the bioavailability of poorly soluble drugs especially inorgans such as the nasal cavity and the rectum where prolongation of thedrug delivery system's residence time can be accomplished relativelyeasily [Hochman J. and Artursson P., J. Contr. Rel., 29:253-267 (1994)].However, data on the enhancement of drug uptake in the GI tract areavailable primarily from in vitro studies. In such kind of studies theabsorption modulator(s) is placed (or perfused in a constant rate) overunreal period of time. Some studies reported on prolongedpharmacological effect [Geary R. S. and Schlameus H. S., J. Contr.Release 23:65-74 (1976); Damge', et al., Diabetes 37:246-251 (1988)].This effect was achieved either when relatively high amounts ofabsorption enhancers were used, or when microparticles and bioadhesiontechniques were employed. Under normal conditions the motility of thesmall intestine pushes a solid dosage form so that it stays very brieflyin the vicinity of the absorbing mucosa. Therefore it is reasonable toassume that a controlled release technology is required to “seed”constant amounts of enhancer(s) along the digestive tube. Yet, theabsorption modulator should be released in a rate similar to the releaserate of the protein drug. The simplest way to achieve such asynchronization would be with a large, erodible dosage form. It will bedifficult for a particulate dosage form to accomplish suchsynchronization because the spreading effect caused by gastric emptyingunder fasted conditions. Table C hereunder summarizes some techniquesfor the oral delivery of peptide drugs based on ordinary controlledrelease concepts.

[0016] When a protein drug is formulated together with an absorptionenhancer and/or peptidase inhibitor into an oral dosage form, the rateof supply of the formulation functional ingredients into the aqueousmilieu of the GI tract becomes crucial. It is important for the releaserates to be slow and controllable [i.e. the release rates of the proteindrug, the peptidase inhibitor(s) and/or the absorption enhancer(s) mustall be slow and synchronized] for the following reasons: (a) To improveits absorption the protein drug should be continuously accompanied byits “guard” molecules, i.e. the peptidase inhibitor or the absorptionenhancer, or both of them, until the drug's absorption has beencompleted; (b) A synchronized slow release from the delivery system willascertain a prolonged drug supply to the body which will result in adesired and sufficient pharmacodynamic response, hereby overcoming thelimitation of the short biological half life of the protein drug, (c) Anuncontrollable, immediate release of the protein drug together with theprotease inhibitor and/or the absorption enhancer (from dosage formssuch as enteric coated capsules, or microcapsules or microparticulatedelivery systems) could cause an unrestrained dilution of the drug withthe fluids of the alimentary canal. This might reduce the concentrationof the drug into values below those required to maintain effectiveconcentration gradients across the intestinal epithelium; (d) Sincevarious formulation components (the protein drug, the absorptionenhancer and the protease inhibitor) differ from each other by theirphysico-chemical properties (solubility, dissolution constants, mode ofdissolution, and partition coefficients) difficulties are likely toarise in the design of an oral delivery system of protein drugs,especially the systems that release their drug content in a burst manner(enteric coated capsules), or rely on diffusion throughout a membrane(microcapsules, coated tablets). TABLE C Examples for controlled releasetechniques for oral delivery of protein drugs relying onnon-synchronized drug diffusion from capsules, microcapsules,microemulsions or erodible polymers TECHNIQUE REFERENCE Colonic deliveryusing insulin-containing soft gelatin Touitou, E. and Rubinstein A.,Int. capsules coated with mixtures of various ratios of J. Pharm. 30:95-99 (1986) polyacrylic polymers having different pH-dependentsolubility properties (Eudragit^(R) RS, L and S) Entrapment of insulinin liposomes that presumable Weingarten, C., et al., Life Sci. providemechanical protection against proteolysis 28: 2747-2751 (1981);Dapergolas G., Gregoriadis G., Lancet 2: 824-827 (1976); Patel H. M.,Ryman B. E., FEBS Lett. 62: 60-63 (1976) Microemulsions (insulin andaprotinin in the aqueous Cho, Y. W. and Flynn, M., Lancet phase, andlecithin, non-esterified fatty acids, and 2: 1518-1519 (1989)cholesterol in the oily phase). For convenience of administration, themicroemulsion was sprayed onto an inert carrier (calciumcarboxymethylcellulose), and placed in hard gelatin capsules Colonicdelivery using mixtures of insulin Kraeling M. E. K. and Ritschel W. A.microemulsions Cab-O-Sil^(R) filled gelatin capsules Meth. Find. Exp.Clin pretreated with formaldehyde vapor and coated with Pharmacol. 14:199-209 (1992) Eudragit NE 30D, Eudragit S100, and finally withcellulose acetate phthalate coat Insulin-containing nanocapsules made ofDamge' C., et al. Diabetes 37: 246-251 polyalkylcyanoacrylate (1988)Insulin and protease inhibitor microspheres that were Morishita, M., etal., Int. J. Pharm. incorporated into an enteric-coating (with Eudragit78: 1-7 (1992) L-100) carrier Colonic delivery of insulin (and alsoSaffran, M., et al., Science lysinevasopressin) using coats ofcopolymers of 233: 1081-1084 (1986) styrene and hydroxyethylmethacrylatecross-linked with azoaromatic groups Micro matrices of poly(d,l-lactide) or PLGA for the Sanders L. M. et al., J. Pharm. Sci.,sustained release of LHRH analogue or interferon 73: 1294, 1984; SandersL. M. et al., J. Contr. Rel. 2:187, 1985

[0017] There are some non-proteinous drugs that suffer from similarconstraints upon oral administration. It is well recognized now that thePhase I metabolic enzyme cytochrome P-450 is active in the intestinalbrush border. In the rat the villus tip cells contain higher amounts ofthis enzyme than the crypt cells, and the enzyme content in the smallintestine is larger than the colon [Hoensch H. et al., Biochem. Biophys.Res. Commun. 65:399-406 (1975)]. A longitudinal gradient of CytochromeP-450 exists also in humans [Peters W. H. M. et al., Gastro-enterology,96:783-789 (1989)]. As a result, drugs such as benzphetamin [Oshinski R.J. and Strobel H. W., Int. J. Biochem. 19:575-588 (1987)] andcyclosporine [Benet L. Z., et al., Proceedings of the 7th InternationalSymposium on Recent Advances in Drug Delivery Systems, Salt Lake City,Utah, pp. 11-14 (1995)] are susceptible to first-pass brush bordermetabolism and their bioavailability is decreased significantly.Appropriate cytochrome P-450 inhibitors such as metyrapone, n-octylamineor propafenone, if formulated in erodible delivery systems as describedabove mars be able to provide reasonable protection to such drugs afteroral ingestion. It is noteworthy that although being an oligopeptide,cyclosporine is not metabolized by the gut peptidases but rather bycytochrome P-450-dependent monooxygenase [Fahr A., Clin. Pharmacokin.24:472-495 (1993)].

[0018] An example for a drug that undergoes brush border metabolismafter oral administration and could benefit from being incorporated intoan erodible delivery system with suitable enzyme inhibitor is morphinewhich is degraded by mucosal glucuronyl transferase. Its bioavailabilityafter oral administration is much lower than after parenteraladministration [Osborne R. et al., Clin. Pharmacol. Ther. 47:12-19(1990)]. TABLE D Examples of drugs that undergo enzymatic degradation inthe intestinal mucosa [Johann W. Faigle, in Colonic Drug Absorption andMetabolism, Peter R. Bieck ed. Marcel Dekker, Inc. New York.Basel.HongKong, p.40 (1993)] SUBSTRATE ENZYME Chlopromazine Cytochrome P-450Ethinylestradiol Cytochrome P-450, sulfotransferase FlurazepamCytochrome P-450 Morphine Glucuronyl tranferase Lorazepam Glucuronyltranferase

[0019] A rational design for an oral delivery system of a protein drugwould therefore be one in which the synchronized release is accomplishedby an erodible matrix. In such a dosage form the release of the proteindrug and the functional adjuvants do not depend upon intrinsic diffusionprocesses but rather are the result of the rate of the matrix erosion.By stripping off the erodible matrix layers in a well controlled mannerpredetermined amounts of the drug and its “guards”, the proteaseinhibitor(s) and the absorption enhancer(s), will be placed togetheralong the desired segment of the GI tract so that constant and optimaldrug blood concentrations are achieved. The successful functioning ofthe matrix tablets depends upon the ability to “fine tune” its erosionrate. Superior performance can be achieved if part of the matrix tabletcomponents are able, by virtue of their own properties, to serve aspeptidase inhibitors. Typical examples of these kinds of polymers arethe loosely crosslinked acrylic polymers Carbopol and polycarbophil(PCP). It has been shown that they provide protection to some peptidedrugs [Borchard G. et al. Proceedings of the 7th International Symposiumon Recent Advances in Drug Delivery Systems, Salt Lake City, Utah, 1995,pp. 7-10, Bai J. P-F., et al., ibid., pp. 153-154]. A major drawback ofthese polymers for the purpose of the suggested technology is theirextremely high swelling properties which cause them to disperse inaqueous solutions within 30 minutes. Therefore a supportive, hydrophobicpolymer such Eudragit^(R) RL must be incorporated into the matrixdelivery system (e.g. by forming a polymer blend) in order to achieve afirm hydrogel which will erode (but not create a diffusional barrier)and to establish a control over the erosion rate of the dosage form.Hydrogel forming materials such as the above mentioned polycarbophil orthe polycarbophil blend with Eudragit^(R) RL must be able to swell inthe GI tract and at the same time erode. If they only swell, they willcreate a diffusional barrier (a conventional sustained releaseformulation) that will risk the synchronized release. For the purpose oferodible matrix hydrogels additional materials can be used. Some goodcandidates for this are saccharidic hydrogels such as natural gums andtheir salts, e.g. alginic acid and its calcium salt—calcium alginate, orpectin and its calcium salt calcium pectinate. If formulated properlythese polysaccharides form hydrogels that exchange ions with the GIphysiological fluids. As a result they lose their mechanical strengthand erode while swelling in a controllable manner.

SUMMARY OF THE INVENTION

[0020] The present invention relates to a controlled release drugdelivery system comprising a drug which is susceptible to enzymaticdegradation by enzymes present in the intestinal tract; and a polymericmatrix which undergoes erosion in the gastrointestinal tract comprisinga hydrogel-forming polymer selected from the group consisting of (a)polymers which are themselves capable of enhancing absorption of saiddrug across the intestinal mucosal tissues and of inhibiting degradationof said drug by intestinal enzymes; and (b) polymers which are notthemselves capable of enhancing absorption of said drug across theintestinal mucosal tissues and of inhibiting degradation of said drug byintestinal enzymes; wherein when the matrix comprises a polymerbelonging to group (b) the delivery system further comprises an agentwhich enhances absorption of said drug across the intestinal mucosaltissues and/or an agent which inhibits degaradation of said drug byintestinal enzymes and when the matrix comprises a polymer belonging togroup (a) the delivery system optionally further comprises an agentwhich enhances absorption of said drug across the intestinal mucosaltissues and/or an agent which inhibits degaradation of said drug byintestinal enzymes.

[0021] The drug delivery system of the invention further provides amethod for orally administering a drug which is susceptible todegradation by enzymes present in the intestine, or mixture of suchdrugs, to a patient in need of such drug.

[0022] The delivery system of the invention provides for the controlledrelease of not only the drug, but also of the inhibitor of thedrug-degrading enzyme and/or the drug absorption enhancer. Thissynchronized release of the enzyme inhibitor and/or the absorptionenhancer furnishes a constant protection against enzymatic degradationof the drug, which is also released from the hydrogel formed by contactwith the physiological fluids in a sustained manner, upon the erosionthereof.

[0023] The invention also relates to a method of preparing thepharmaceutical delivery system according to the invention.

DESCRIPTION OF THE FIGURES

[0024]FIG. 1: Pictorial scheme of the erodible hydrogel solid platformconcept for the oral delivery of large molecular weight drugs or drugssusceptible to enzymatic degradation in the GI tract.

[0025]FIG. 2: Erosion rates of PCP tablets and two types of tablets madeof blends of different ratios of PCP and Eudragit^(R) RL (PCP containing5% Eudragit^(R) PL and PCP containing 10% Eudragit^(R) RL) in aphosphate buffer, pH 6.8.

[0026]FIG. 3: The steady state swelling properties of PCP films andfilms made of different ratios of PCP-Eudragit^(R) RL blends inphosphate buffer pH 7.5.

[0027]FIG. 4: The torsion force of different PCP-Eudragit^(R) RL blendsin swollen, steady state.

[0028]FIG. 5: Para-nitrophenol β-glucopyranoside (PNP-β-glucopyranoside)degradation kinetics resulted by incubation with β-glucosidase inaqueous solution and in the presence of two concentrations of PCP and amixture of PCP and Eudragit^(R) RL.

[0029]FIG. 6: The inhibition of bradykinin degradation by 0.5% w/v PCPsuspension.

[0030]FIG. 7: A: Mean blood insulin levels and the resulting glucoselevels after oral administration of calcium pectinate (CaP) tabletscontaining (a) 600 I.U. of insulin, (b) 40 mg of soy bean trypsin (SB-n)inhibitor and (c) 100 mg of sodium cholate to three pancreatectomizeddogs. Shown are the mean values±S.D.

[0031] B: Mean blood insulin levels after oral administration of lactosetablets containing (a) 600 I.U. of insulin, (b) 40 mg of soy beantrypsin (SeI) inhibitor and (c) 100 mg of sodium cholate to threepancreatectomized dogs. Shown-are the mean values±S.D.

DETAILED DESCRIPTION OF THE INVENTION

[0032] It is suggested that the in vivo formation of an erodiblehydrogel, which contains a drug which may be susceptible to enzymaticdegradation, an inhibitor of the enzyme/s which may degrade said drugand an agent which enhances the absorption of said drug acrossintestinal mucosa, in the presence of physiological fluids of thegastrointestinal (GI) tract, particularly in the intestine, upon oraladministration, causes a simultaneous release of the entrapped drug, theenzyme inhibitor and the absorption enhancer. This, in turn, wouldinhibit the enzymatic degradation of the drug and facilitate itsabsorption. Therefore, matrix dosage forms incorporating a suitablehydrogel-forming polymer, a drug which is susceptible to enzymaticdegradation or a high molecular weight drug (such as protein drug), anenzyme inhibitor (such as protease inhibitor) and an absorption enhancermay serve as a platform for sustained oral delivery system of suchdrugs.

[0033] The drug delivery system of the invention is schematicallyillustrated in FIG. 1 which is a pictorial scheme of the erodiblehydrogel solid platform concept for the oral delivery of large molecularweight drugs or drugs susceptible to enzymatic degradation in the GItract. FIG. 1A shows a non-synchronized delivery system, which can be ineither of the following dosage forms: (a) A capsule which dissolvesrapidly and releases its contents immediately. As a result the drug (D),the enzyme inhibitor (PI) and the absorption enhancer (AE) are dilutedin the intestinal contents, dissolve in individual rates and cannotsupply protection or supportive absorption enhancement to the drug. (b)A coated tablet or microcapsules, in which the protective coat creates adiffusional barrier. In this case each one of the dosage form componentswill leach out of the dosage form at a different rate causing the drugto remain without its functional adjuvants in the intestinal milieu. (c)An erodible hydrogel which erodes while moving along the digestive tuberesulting in a synchronized release of the drug, the enzyme inhibitorand the absorption enhancer. The simultaneous release depends on theerosion rate of the carrier and not on the physico-chemical propertiesof the ingredients. In this technology the enzyme inhibitor or theabsorption enhancer could be the hydrogel itself. The erosion dependentrate of the components release will result in a similar effect asdescribed in FIG. 1B.

[0034] Thus, the present invention relates to a controlled release drugdelivery system comprising a drug which is susceptible to enzymaticdegradation by enzymes present in the intestinal tract; and a polymericmatrix which undergoes erosion in the gastrointestinal tract comprisinga hydrogel-forming polymer selected from the group consisting of (a)polymers which are themselves capable of enhancing absorption of saiddrug across the intestinal mucosal tissues and of inhibiting degradationof said drug by intestinal enzymes; and (b) polymers which are notthemselves capable of enhancing absorption of said drug across theintestinal mucosal tissues and of inhibiting degradation of said drug byintestinal enzymes; wherein when the matrix comprises a polymerbelonging to group (b) the delivery system further comprises an agentwhich enhances absorption of said drug across the intestinal mucosaltissues and/or an agent which inhibits degradation of said drug byintestinal enzymes and when the matrix comprises a polymer belonging togroup (a) the delivery system optionally further comprises an agentwhich enhances absorption of said drug across the intestinal mucosaltissues and/or an agent which inhibits degradation of said drug byintestinal enzymes.

[0035] The major utility of the delivery system according to theinvention is for the oral delivery of peptide drugs. However, it alsocan be used for the delivery of non-proteinous, poorly absorbed drugs ordrugs that are susceptible to brush border metabolism.

[0036] In one aspect, the invention relates to a controlled release oraldrug delivery system comprising a drug which is susceptible to enzymaticdegradation in the intestine and a polymeric matrix comprising ahydrogel-forming polymer which by virtue of its own properties can serveas an absorption enhancer or enzyme inhibitor or both, namely polymersbelonging to the said group (a).

[0037] Examples of said group (a) polymers are hydrogel-forming polymerswhich exhibit properties of enzyme inhibition and enhancement of drugabsorption acrylic acid, acrylic acid derivatives or combinationsthereof. Preferred such polymers are acrylic acid derivatives such aspolycarbophil or Carbopol.

[0038] In a second aspect of the invention, and of the same concept, iscontrolled release drug delivery system in which the matrix comprises apolymer selected from said group (b). In embodiments according to thisaspect of the invention the polymeric matrix comprises, apart from thepolymer and drug entrapped therein, at least one agent which is capableof inhibiting enzymatic degradation of the drug in the intestine and atleast one agent which enhances the absorption of the drug acrossintestinal mucosal tissues.

[0039] The group (b) hydrogel-forming polymer may be cellulosederivatives, for example, methylcellulose, carboxymethyl cellulose orhydroxypropyl cellulose, acrylic acid or acrylic acid derivatives, forexample methylmethacrylate, or a combination thereof. Thehydrogel-forming polymer may be a blend of polymers (for example, ablend of polycarbophil and Eudragit^(R) RL-100). Alternatively, thehydrogel-forming polymer may be a natural polymer, for example guar gum,acacia gum, agar, tragacanth, alginic acid, dextran, arabinogalactan,pectin, egg albumin, soybean protein or hyaluronic acid. Thehydrogel-forming polymer may also be a modified natural polymer, forexample calcium pectinate, calcium alginate, modified egg albumin ormodified soybean protein.

[0040] Naturally, delivery systems according to the invention in whichthe hydrogel-forming polymer belongs in said group (a), may also furtheroptionally comprise at least one agent which inhibits enzymaticdegradation of the drug in the intestine and/or at least one agent whichis capable of enhancing the absorption of the drug across the intestinalmucosa.

[0041] In the drug delivery system of the invention, said matrix maycomprise said hydrogel-forming polymer and at least one additionalpolymer. Examples of such additional polymers are hydrophobic acrylicacid derivatives such as Eudragit^(R) RL, or suitable hydrogel-formingpolymers such as hydroxypropylmethyl cellulose, methylcellulose,carboxymethyl cellulose or hydroxypropyl cellulose, or combinationsthereof, natural polymers, such as guar gum, acacia gum, agar,tragacanth, alginic acid, dextran, arabinogalactan, pectin, egg albumin,soybean protein or hyaluronic acid, modified natural polymers, such ascalcium pectinate, calcium alginate, modified egg albumin or modifiedsoybean protein.

[0042] When emloying an absorption enhancer, this may be amedium-chained fatty acid, such as octanoic acid and decanoic acid, afatty acid derivative such as palmitoyl-DL-carnitine orN-myristoyl-L-propyl-L-prolyl-glycinate, a non-steroidalantiinflammatory drug such as sodium salicylate, sodium5-methoxysalicylate, indomethacin, diclofenac, a nonionic surfactant,such as polyoxyethylene ether, an anionic surfactant, such as sodiumlaurylsulfate, a cationic surfactant, such as a quaternary ammoniumcompound, a dihydroxy bile salt, such as sodium deoxycholate, atrihydroxy bile salt, such as sodium cholate, a medium-chain glyceride,such as glyceryl-1-monooctanoate, an enamine, such as DL-phenylalanine,ethyl-acetoacetate enamine, mixed micelles such as glycerylmonooleate+sodium taurocholate or linoleic acid+HCO60, a calcium bindingagent, such as EDT A, a phenothiazine, such as chlorpromazine,liposomes, azone, a saponin, such as concanavaline, or a phosphate andphosphonate derivative, such as DL-α-glycerophosphate or3-amino-1-hydroxypropylidene-1,1-diphosphonate. Other absorptionenhancers are also possible, and are known to the man versed in the art.

[0043] When adding an er me inhibitor, the inhibitor is suited to thedrug entrapped in the matrix. Thus, for matrices containing protein orpeptide drugs, the inhibitor may be any suitable protease inhibitor, forexample, soybean trypsin inhibitor, aprotinin,diisopropylfluorophosphate, a-aminoboronic acid, sodium glycocholate orα-1-antitrypsin. Other protease inhibitors, as known to the man of theart may be suitable.

[0044] For matrices containing a drug which is susceptible todegradation by Cytochrome P-450, such as chlopromazine and flurazepam,the inhibitor may be any suitable cytochrome P-450 inhibitor, forexample n-octylamine or propafenone. Other cytochrome P-450 inhibitors,as known to the man of the art may be suitable.

[0045] For matrices containing a drug which is susceptible todegradation by glucuronyl transferase, such as lorazepam or morphine,the inhibitor may be any suitable glucuronyl transferase inhibitor, forexample an OH donor such as bilirubin. Other typical gulcuronylinhibitors are tricyclic depressants, such as amiyriptriptyline,nortriptyline, comipramine or fluoxetin, in sub-therapeuticalconcentrations of 10⁻⁶M [Wahlstrom, A., et al. Pharmacology & Toxicology75: 23-27 (1994)]. Another specific inhibitor is the novel site-directedinhibitor DHPJAdU [Pattaglya, E. et al., Biochem. Biophys. Acta1241:9-14 (1995)].

[0046] The drug may be a protein drug may be any protein or peptidedrug, for example, calcitonin, cyclosporin, insulin, oxytocin, tyrosine,enkephalin, tyrotropin releasing hormone (TRH), follicle stimulatinghormone (FSH), luteinizing hormone (LH), vasopressin and vasopressinanalogs, catalase, superoxide dismutase, interleukin-II (IL2),interferon, colony stimulating factor (CSF), tumor necrosis factor (TNF)or melanocyte-stimulating hormone. Other peptide or protein drugs, asknown to the man skilled in the art, may also be contained in thepharmaceutical delivery system of the invention. Mixtures of the drugsare also contemplated.

[0047] The delivery system of the invention is also suitable for thedelivery of drug other than protein or peptide drugs, which aresusceptible to degradation by enzymes present in the intestine or in theintestinal mucosa. Examples of such drugs are cyclosporin,chlopromazine, ethinylestradiol and flurazepam, which are degraded bycytochrome P-450, and lorazepam and morphine, which are susceptible todegradation by glucuronyl transferase.

[0048] Other drugs, as known to the man skilled in the art, may also becontained in the pharmaceutical delivery system of the invention.

[0049] In addition to the above constituents, the different embodimentsof the pharmaceutical delivery system according to the invention mayalso contain pharmaceutically acceptable adjutants.

[0050] The drug delivery system according to the invention is preferablyin oral dosage unit form. Specific embodiments of prepared formulationsof the protein drug delivery system of the invention include, forexample, plain matrix tablets, especially tablets prepared bycompression, multi-layered tablets or multi-particulate formulations,such as pellets or matrix-drug nanoparticles, which may be free orpacked in gelatin capsules or any other means allowing oraladministration. Techniques for preparation of such formulations are wellknown in the art, for example, as described in Remington'sPharmaceutical Sciences, Mack Publishing Company, 16th edition, 1980. Inall embodiments, more than one drug may be supplied to the patient inthe same matrix.

[0051] The oral dosage forms according to the invention may optionallybe coated with another polymer for the purpose of increasing theproducts stability upon storage or a suitable enteric coating materialto protect it from the acidic environment of the stomach, as known tothe man skilled in the art.

[0052] The therapeutic benefits of orally administered drugs, such asorally administered protein drugs, may depend upon the effective amountof the drug which is absorbed in the intestines of the patient. Thedelivery system according to the invention greatly increases the amountof intact drug, not degraded by the various enzymes present in theintestinal tract, which is absorbed. In addition, with most of drugs,controlled release, and thus absorption over long periods of time, isadvantageous. The delivery system of the invention provides for suchcontrolled release of the drug.

[0053] The amount of the drug can vary as desired for efficaciousdelivery of the desired drug and in consideration of the patient's age,sex, physical condition, disease and other medical criteria. Inaddition, the amount of the drug delivered by the system of theinvention will depend upon the relative efficacy of the drug. The amountof specific drug necessary for efficacious results in the deliverysystem and methods of the invention may be determined according totechniques known in the art. For example, recommended dosages such asknown in the art (for example, see the Physician's Desk Reference, 1991(E. R Barnhart, publisher). The Merck Index, 10th Edition, Merck & Co.,New Jersey and The Pharmacological Basis of Therapeutics, 8th Edition,A. G. Goodman et al., eds., Pergamon Press, New York), provide a basisupon which to estimate the amount of drug which has previously beenrequired to provide an efficacious level of activity.

[0054] The drug delivery system of the invention further provides amethod for orally administering a drug to a patient in need thereof. Inaddition to the administration of protein or peptide drugs, theinvention further provides a method for orally administeringnon-proteinous drugs having low bioavailability upon oral administrationdue to their high molecular weight (above 1,000 Da), or due to theirsusceptiblity to brush border metabolism, or mixture of such drugs, to apatient in need thereof.

[0055] The invention also relates to a method of preparing thepharmaceutical delivery system according to the invention.

[0056] According to one specific embodiment the method of preparation ofthe delivery system according to the invention comprises the steps of(a) dissolving or suspending separately said hydrogel-forming polymer/sin non-aqueous media such as methanol; (b) in case two polymers are usedmixing the two polymer solutions\suspensions obtained in step (a)-(c)drying the mixtures obtained in step (b) into films; (d) grinding thedry films obtained in step (c); (e) suspending the ground mixturesobtained in step (d) in aqueous solution containing the drug andoptionally the enzyme inhibitor and the absorption enhancer(s); (f)lyophilizing the mixture obtained in step (e); and (g) compressing thedry lyophilized polymer—drug mixture obtained in step (f) into dosageunit forms.

[0057] The following examples further describe the materials and methodsuseful in carrying out the invention. The examples in no manner areintended to limit the invention, which is defined by the scope of theappended claims.

EXAMPLES

[0058] Preparation of PCP—E-RL Hydrogels

[0059] Different polycarbophil (PCP)— Eudragit^(R)-RL (E-RL) blends wereprepared in different experiments by dissolving different (increasing)amounts of E-RL in methanol. This was followed by the addition of aconstant amount. (0.5 g) of PCP under stirring. The formed suspensionswere then stirred until a homogenous, low-viscous gels were formed. Thegels were poured onto a flat surfaces (petri dish), that were driedfirst at room temperature and then at 50° C. for 24 hours until thinfilms containing blends of different PCP—E-RL ratios were formed. Theproducts were characterized for physical properties. Some of theproperties were analyzed in film form (swelling, modulus of elasticity,torsion force) and some after tabletting (erosion, which was measuredgravimetrically in PBS pH=7.5, relative to the dry weight of thetablets). The dependency on the E-RL contents in the gel blends and thetorsion force was assessed from the best fitted line by using non linearregression.

[0060] The ability of Eudragit^(R) RL to modify the properties of thehydrogel is illustrated in FIGS. 2 to 4.

[0061] Thus, the ability of Eudragit^(R) RL to control the erosion ratesof the hydrogel is illustrated in FIG. 2 which demonstrates that acontrol over the erosion rate is accomplished by incorporatingincreasing amounts of Eudragit^(R) RL into the PCP tablet.

[0062] The ability of Eudragit^(R) RL to control the steady stateswelling properties of the hydrogel is shown in FIG. 3 whichdemonstrates that Eudragit^(R) RL significantly decreases the swellingproperties of PCP and that the swelling is controllable by altering theEudragit^(R) RL amounts in the blends.

[0063] The ability of Eudragit^(R) RL to control the torsion force ofdifferent PCP-Eudragit^(R) RL blends in swollen, steady state is shownin FIG. 4 which demonstrates that Eudragit^(R) RL increases, in acontrollable manner, the torsion force of PCP in swollen blends of PCPand Eudragit^(R) RL.

[0064] The ability of Eudragit^(R) RL to control the modulus ofelasticity of the hydrogel is summarized in Table 1. TABLE 1 The modulusof elasticity (as characterized by Youngs modulus values) of differentPCP-Eudragit^(R) RL blends in swollen, steady state. Concentration ofEudragit^(R) RL in the blend (% w/W 0 5 10 20 50 75 Modulus ofelasticity 1,272 2,041 5,302 5,941 6,561 18,190 (g × cm²)

[0065] The Table demonstrates that Eudragit^(R) RL increases, in acontrollable manner, the Youngs modulus of PCP in swollen blends of PCPand Eudragit^(R) RL.

[0066] The ability of PCP and PCP together with E-RL to protect theglucosidic substrate p-Nitrophenol-β-D-glucopyranoside (pNPG) againstβ-glucosidase was measured in aqueous suspensions of elevatedconcentrations of PCP (0.1% w/v and 0.2% w/v) and (in separate study) inPCP suspension (0.1% w/v) containing 5% w/v of E-RL.

[0067] It was found that PCP was able to protect pNPG against enzymaticdegradation in non-compatible manner and that E-RL did not interferewith this inhibition. As may be seen i9n FIG. 5, PCP is capable ofinhibiting the activity of β-glucosidase in a concentration dependentmanner and Eudragit^(R) RL does not interfere with the inhibitionactivity of PCP. The kinetic profiles shown in FIG. 5 indicate that theinhibition of β-glucosidase by PCP is non-specific.

[0068] The Effect of PCP on the Enzymatic Degradation of Bradykinin

[0069] Fifty mg of bradykinin (Sigma) was incubated (37° C.) togetherwith 0.5% w/w PCP suspension (pH 3.2). After 10 minutes 1 I.U. ofα-chymotrypsin (Sigma) was added to the mixture and the incubationproceeded for additional 120 minutes.

[0070] Almost no bradykinin degradation could be detected. It is assumedthat the α-chymotrypsin inhibition was caused by the acidic pH createdby the PCP. It is assumed that if bradykinin will be mixed together withPCP to create a solid dosage form the resulted hydrogel which will beformed upon contact with water will provide a local protection (becauseof the formation of local low pH environment) to this protein drugagainst pancreatic enzymes [Lee V. H. L., CRC Crit. Rev. in Ther. DrugCarrier Systems, 5-69-139 (1989)].

[0071] As may be seen in FIG. 6, PCP is able to inhibit the activity ofα-chymotrypsin and hence to protect bradykinin from degradation.

[0072] Preparation of CaP-I Mixtures and Tablets

[0073] Insulin, sodium cholate (SC) and soybean trypsin inhibitor (SBTI)were mixed with 100 ml of the rinsed CaP gel [Rubinstein A. et al.,Pharm. Res., 10:258, (1993)] in a dialysis bag prior to drying. Theamount-ratio of the SC, SBTI and insulin to CaP was adjusted so that 500mg of dry CaP contained 600 I.U. of insulin, 40 mg of SBTI and 100 mg ofSC. The gel was lyophilized and the resulting dry CaP containinginsulin, SC and SBTI was collected, comminuted to a fine powder, andsealed at 4° C. until further processing. Tablets were prepared from thedried gel powder. The plain matrix tablets were composed of 360 mg ofCaP-insulin, 100 mg of SC and 40 mg of SBTI pressed at 5 KgP (PerkinElmer manual press) to give a 500 mg tablet containing 600 I.U. ofinsulin each.

[0074] Preparation of Lactose-I Tablets

[0075] Lactose-I tablets were composed of 360 mg lactose-1,100 mg sodiumcholate (SC) and 40 mg soybean trypsin inhibitor (SBTI) pressed at 5 KgPto give a 500 mg tablet containing 600 I.U. of insulin.

[0076] In Vivo Analysis of the Insulin-CaP Tablets in Dogs

[0077] Three mongrel dogs, weighing between 25 and 30 Kg werepancreatectomized, to achieve an immediate response to blood insulinalterations, and maintained on a daily intramuscularly introducedinsulin. In three different experiments, CaP-I tablets were administeredorally to the dogs. Each administration was performed after an overnightfast. No intramuscular insulin was administered on the morning of theexperiments. At pre-determined time intervals (every whole hour) bloodsamples were withdrawn from the cephalic vein of the dogs. This includeda sampling one hour before each study (time 0).

[0078] Results

[0079] The blood and glucose levels after oral administration of thetablets are shown in FIG. 7a. This Figure clearly demonstrates that theuse of an erodible hydrogel matrix (in this case unprotected CaP) with aprotein absorption enhancer (in this case sodium cholate) and a proteasedegradation inhibitor (in this case (SBTI) results in sustained releaseof insulin, thus achieving constant levels of portal blood insulin. As aresult, prolonged pharmacological response (over eight hours of reducedglucose levels) was achieved.

[0080] When tablets of the same composition, but with lactose instead ofCaP were tested in the same dogs, typical non-sustained reduction inblood glucose levels was obtained (FIG. 7b). These results were expectedsince lactose dissolves in the GI fluids and does not form a hydrogel.

What is claimed is:
 1. A synchronous drug delivery compositioncomprising: a polymeric matrix which comprises 1) An acrylic acidderivative, wherein said acrylic acid derivative is blended with ahydrophobic polymer, so as to form an erodible matrix; 2) a drug;wherein erosion of said erodible matrix, permits synchronous release ofsaid drug and said acrylic acid derivative.
 2. A synchronous drugdelivery composition comprising: a polymeric matrix which comprises 1)acrylic acid derivative, wherein said acrylic acid derivative is blendedwith a hydrophobic polymer, so as to form an erodible matrix; 2) a drug;and 3) an agent which enhances intestinal drug absorption; whereinerosion of said erodible matrix permits synchronous release of said drugand said agent.
 3. A synchronous drug delivery composition comprising: apolymeric matrix which comprises 1) acrylic acid derivative, whereinsaid acrylic acid derivative is blended with a hydrophobic polymer, soas to form an erodible matrix; 2) a drug; and 3) an agent which inhibitsintestinal drug degradation; wherein erosion of said erodible matrixpermits synchronous release of said drug and said agent.
 4. Asynchronous drug delivery composition comprising: a polymeric matrixwhich comprises 1) acrylic acid derivative, wherein said acrylic acidderivative is blended with a hydrophobic polymer, so as to form anerodible matrix; 2) a drug; 3) an agent which inhibits intestinal drugdegradation; and 4) an agent which enhances intestinal drug absorption;wherein erosion of said erodible matrix permits synchronous release ofsaid drug, said agent which enhances drug absorption and said agentwhich inhibits drug degradation.
 5. A pharmaceutical compositioncomprising the synchronous drug delivery composition of claim 1 and acarrier or diluent.
 6. A pharmaceutical composition comprising thesynchronous drug delivery composition of claim 2 and a carrier ordiluent.
 7. A pharmaceutical composition comprising the synchronous drugdelivery composition of claim 3 and a carrier or diluent.
 8. Apharmaceutical composition comprising the synchronous drug deliverycomposition of claim 4 and a carrier or diluent.
 9. A drug deliverycomposition according to claim 1, wherein the composition is in the formof a plain matrix tablet.
 10. A drug delivery composition according toclaim 2, wherein the composition is in the form of a plain matrixtablet.
 11. A drug delivery composition according to claim 3, whereinthe composition is in the form of a plain matrix tablet.
 12. A drugdelivery composition according to claim 4, wherein the composition is inthe form of a plain matrix tablet.
 13. A drug delivery compositionaccording to claim 1, wherein the composition is in the form of amultilayer tablet.
 14. A drug delivery composition according to claim 2,wherein the composition is in the form of a multilayer tablet.
 15. Adrug delivery composition according to claim 3, wherein the compositionis in the form of a multilayer tablet.
 16. A drug delivery compositionaccording to claim 4, wherein the composition is in the form of amultilayer tablet.
 17. A drug delivery composition according to claim 1,wherein the composition is coated with an enterocoating.
 18. A drugdelivery composition according to claim 2, wherein the composition iscoated with an enterocoating.
 19. A drug delivery composition accordingto claim 3, wherein the composition is coated with an enterocoating. 20.A drug delivery composition according to claim 4, wherein thecomposition is coated with an enterocoating.
 21. A method ofsynchronically release a drug and an agent which enhances intestinaldrug absorption comprising the step of administering the composition ofclaim
 2. 22. A method of synchronically release a drug and an agentwhich inhibits intestinal drug degradation comprising the step ofadministering the composition of claim
 3. 23. A method of synchronicallyrelease a drug, an agent which inhibits intestinal drug degradation andan agent which enhances intestinal drug absorption comprising the stepof administering the composition of claim
 4. 24. A method of increasingthe bioavailability of a drug comprising the step of administering thedrug delivery composition according to claim
 1. 25. A method ofincreasing the bioavailability of a drug comprising the step ofadministering the drug delivery composition according to claim
 2. 26. Amethod of increasing the bioavailability of a drug comprising the stepof administering the drug delivery composition according to claim
 3. 27.A method of increasing the bioavailability of a drug comprising the stepof administering the drug delivery composition according to claim 4.